Cobimetinib/Vemurafenib Combo Improves Survival in Melanoma

The combination of vemurafenib and cobimetinib demonstrated a statistically significant improvement in overall survival compared with vemurafenib alone for previously untreated patients with BRAFV600-mutant unresectable or metastatic melanoma.

Michael M. Morrissey, PhD

The combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib demonstrated a statistically significant improvement in overall survival (OS) compared with vemurafenib alone for previously untreated patients with BRAFV600-mutant unresectable or metastatic melanoma, according to new findings from the coBRIM study.

In previous data from the phase III study, the combination of vemurafenib and cobimetinib demonstrated a 5-month improvement in progression-free survival (PFS) compared with vemurafenib plus placebo. This benefit translated to a 42% reduction in the risk of progression or death. OS data and long-term safety findings are being prepared for presentation at an upcoming medical meeting.

“The positive effect of the combination of cobimetinib and vemurafenib on overall survival is a major step forward for patients with advanced BRAFV600 mutation-positive melanoma in search of new treatment options,” Michael M. Morrissey, PhD, president and chief executive officer of Exelixis, the developer of cobimetinib, said in a statement. “We continue to work with our partners at Genentech in preparation for the potential US approval and launch of cobimetinib to deliver this important potential treatment option to patients, physicians and caregivers in the United States as quickly as possible.”

The FDA is currently reviewing data from the coBRIM study as part of a new drug application for the combination of cobimetinib and vemurafenib in melanoma. Under the Prescription Drug User Fee Act, the agency is scheduled to make a decision regarding this submission by November 11, 2015.

In the phase III international coBRIM trial, 495 previously untreated patients were randomized to continuous vemurafenib at 960 mg twice daily plus placebo (n = 248) or cobimetinib at 60 mg once daily on days 1-21 of a 28-day cycle (n = 247). Patient demographics were well balanced across the two arms for age, ECOG performance status, geographic region, and disease stage. More than half of patients had stage IV, M1c melanoma.

PFS was the primary endpoint of the study. Secondary outcome measures included overall survival (OS), objective response rate (ORR), duration of response, and safety.

In findings presented at the 2015 ASCO Annual Meeting from a median follow-up of 14.2 months,1 the median PFS with cobimetinib and vemurafenib was 12.25 months compared with 7.2 months for vemurafenib and placebo (HR, 0.58; 95% CI, 0.460-0.719). A similar improvement in PFS was seen across subgroups, including those with the V600E and K mutations and for those with normal and elevated serum LDH levels.

The ORR was 69.6% versus 50%, for cobimetinib/vemurafenib and vemurafenib/placebo, respectively. The absolute difference in ORR between the two arms was 19.64% (95% CI, 10.95-28.32). The complete response rate in the combination arm was 15.8% versus 10.5% with vemurafenib and placebo. The median duration of response was 12.98 months versus 9.23 months, with cobimetinib and placebo, respectively.

In an earlier analysis of the study published in The New England Journal of Medicine,2 the most frequently reported adverse events (AEs) of all grades reported in the cobimetinib arm versus the control arm included diarrhea (57% vs 28%), nausea (39% vs 24%), photosensitivity (28% vs 16%), increased ALT (24% vs 18%), increased AST (22% vs 13%), increased CPK (30% vs 3%), vomiting (21% vs 12%), and serous retinopathy (20% vs <1%).

Some AEs occurred at lower rates in the combination group, including hair loss (14% vs 29%), hyperkeratosis (10% vs 29%), joint pain (33% vs 40%), cutaneous squamous cell carcinomas (3% vs 11%), and keratoacanthomas (<1% vs 8%).

Treatment-related discontinuation rates in the combination and control groups were similar at 13% and 12%, respectively. There were six deaths related to AEs in the cobimetinib arm and three in the control arm.

“Updated coBRIM efficacy data, now with a median follow-up of 14.2 months, confirmed the clear and definitive clinical benefit of adding cobimetinib to vemurafenib in BRAFV600-mutated melanoma,” lead investigator James Larkin, MD, PhD, medical oncologist at the Royal Marsden Hospital, said during a presentation of the results at the ASCO meeting. “This study continues to follow patients for overall survival. We hope and expect that the final overall survival analysis will occur near the end of this year.”

In addition to the coBRIM study, long-term findings were presented at the ASCO meeting for the single-arm phase Ib BRIM7 trial, which also explored vemurafenib and cobimetinib in advanced melanoma.3 In this study, 129 patients with unresectable or metastatic melanoma received the therapies in a dose escalation arm followed by cobimetinib daily at 60 mg for 21 days and vemurafenib at 720 mg or 960 mg twice daily in a 28-day cycle. Patients in this study were both vemurafenib pretreated and BRAF inhibitor-naive (49%).

For those in the BRAF-naive group, the median follow-up was 21 months. For this group, the median OS was 28.5 months and the 2-year OS rate was 61%. Confirmed responses were seen in 87% of patients treated with the combination, including a complete response rate of 10%.

In those who received prior vemurafenib, the response rate was 15%, with 1 patient achieving a complete response. The 2-year OS rate in this group was 15% and the median OS was 8.4 months, at an 8-month median follow-up.

“These results are exciting because they underscore the importance of combining medicines that target the signals, which cause about half of all melanomas to grow," Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech, the company manufacturing vemurafenib, said in a statement when data from both studies were released at ASCO.

Genentech submitted the new drug application for the combination, which initially received a priority review designation from the FDA in February 2015. Based on the submission of new data; however, the review was delayed by 3 months to the current November action date.

Exelixis announced the delay and the updated OS information. An application for marketing authorization is also pending with the European Medicines Agency, according to the companies.


  1. Larkin JMG, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol. 2015;33 (suppl; abstr 9006).
  2. Larkin JMG, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876.
  3. Pavlick AC, Ribas A, Gonzalez R, et al. Extended follow-up results of phase Ib study (BRIM7) of vemurafenib (VEM) with cobimetinib (COBI) in BRAF-mutant melanoma. J Clin Oncol. 2015;33 (suppl; abstr 9020).